Energy metabolism in the body is controlled by insulin produced by pancreatic beta-cells. Insulin plays an important role in controlling the blood sugar level by affecting and promoting the peripheral tissues or cells to take up sugar from the blood. However, insulin sensitivity of the cells is reduced by continuous intake of high caloric diet, an increase in the blood sugar level as well as oversecretion of insulin proceed at the same time. As a result, pancreatic beta-cells are worn out and thus become dysfunctional, thereby causing diabetes or obesity.
Secretion of insulin is regulated by various hormones. In particular, glucagon-like peptide-1 (GLP-1), produced and secreted in the gastrointestinal tract, is considered important. GLP-1 is a peptide hormone with a molecular weight of about 4,000, which is mainly produced in L cells in the small intestine. GLP-1 has been found to have an effect of promoting insulin secretion by beta-cells, effects of suppressing peristalic movement, digestion and absorption of the stomach, effects of suppressing on appetite and overeating, and else, and thus effective in preventing or treating diabetes or obesity. Since diabetes and obesity decreases GLP-1 production capacity, promotion of GLP-1 production in these pathological conditions is expected to result in prevention or treatment of diabetes or obesity. Although production of GLP-1 in L cells is promoted by intake of various nutrients such as carbohydrate, fat, protein and the like, it is a rare case to apply a compound such as a peptide having a certain component as a GLP-1 secretion promoter.
Cholecystokinin (CCK) is a peptide hormone having a molecular weight of about 4,000, which is mainly produced in L cells of the duodenum and small intestine and which promotes secretions of bile and pancreatic digestive juice. CCK has physiological effects such as an effect of suppressing gastric emptying of food, an effect of promoting pancreatic enzyme secretion and an effect of suppressing food taking due to a sense of fullness (Non-patent documents 1 and 2). Furthermore, CCK is also known to have an effect of promoting secretion of insulin, i.e., a blood sugar regulating hormone (Non-patent documents 3 and 4). CCK having such effects is considered to be promising for treating or preventing lifestyle-related diseases such as diabetes or obesity.
In order to apply peptides GLP-1 and CCK to treatment, intravascular administration such as injection is employed, which is impractical in terms of complication caused by daily administration and large expense. Meanwhile, to make use of the mechanism where endogenous GLP-1 and CCK are secreted from GLP-1- and CCK-producing cells in the small intestine mucosa seems to be worthy of consideration. Specifically, development of a compound or the like that has an effect of promoting GLP-1 and CCK secretions has been awaited.
The calcium receptor, also called the calcium sensing receptor (also referred to as “CaSR”), was cloned from bovine thyroid in 1993 as G-protein coupled seven-transmembrane receptor (G-protein coupled receptor; GPCR) that senses extracellular calcium (Ca2+) (Non-patent Document 5). The calcium receptor has a function of altering the intracellular Ca2+ concentration by sensing extracellular Ca2+, thereby regulating production of hormones or the like involved in Ca2+ metabolic regulation, as typified by parathyroid hormone.
Recently, cinacalcet (CCT), a calcium receptor agonist, was found to have an effect of suppressing secretion of parathyroid hormone by acting on the calcium receptor of parathyroid to enhance Ca2+ sensitivity of the calcium receptor (Non-patent Document 6), and it has been marketed as a therapeutic drug for secondary hyperparathyroidism in dialysis patients (Non-patent Document 7).
In addition, the calcium receptor was also found to be expressed in kidney, brain, thyroid, bones and gastrointestinal tracts, and thus considered to be involved in various diseases.
As compounds having a CaSR activating effect, for example, gamma-glutamyl peptide derivatives are known (Patent Documents 1 and 2), which have also been reported to be effective as a therapeutic agent for diabetes or obesity (Patent Document 3).
These compounds, however, are structurally different from the alkylamine derivatives of the present invention.
On the other hand, a gamma-glutamyl anilide derivative, among the alkylamine derivatives, is known to be used as a substrate for enzymatic activity (Non-patent Document 8) as well as for its application as an antimicrobial agent or an anti-allergic agent (Non-patent Document 9 and Patent Document 4) and its application as an analytical reagent (Non-patent Documents 10 and 11). Moreover, an L-2-amino-3-N′-substituted ureidopropanoic acid derivative is known for its application as a synthetic intermediate of an asparagine analog employed as an anticancer agent (Non-patent Document 12). The alkylamine derivative is known as a leukotriene A4 inhibitor for application against inflammatory diseases (Non-patent Document 13). The alkylamine derivative is also known for its application as an anticancer agent (Non-patent Document 14).
The above-mentioned compounds, however, have not been known for their applications as pharmaceutical agents having a CaSR agonist effect, in particular, an effect of promoting GLP-1 and CCK secretions.